1. Field of the Invention
The present invention relates to cellular compositions and methods for inducing an immune response to tumor cells. The cellular compositions comprise cells that have been genetically modified to express an anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibody and a cytokine, whereby the local, sustained cell-based expression of the anti-CTLA4 antibody at the immunization site significantly reduces the therapeutic concentration compared to systemic administration.
2. Background of the Technology
One therapeutic approach to cancer is the use of autologous or allogeneic cancer cells as vaccines to augment anti-tumor immunity (Oettgen et al., The History of Cancer Immunotherapy, In: Biologic Therapy of Cancer, Devita et al. (eds.) J. Lippincot Co., pp 87-199, 1991; Armstrong T D and Jaffee E M, Surg Oncol Clin N Am. 11(3):681-96, 2002 and Bodey B et al., Anticancer Res 20(4):2665-76, 2000). An expansion of this approach involves the use of genetically modified tumor cells that express cytokines locally at the immunotherapy site.
Numerous cytokines have been shown to play a role in regulation of the immune response to tumors. For example, U.S. Pat. No. 5,098,702 describes use of combinations of TNF, IL-2 and IFN-beta in synergistically effective amounts to combat existing tumors. U.S. Pat. Nos. 5,078,996, 5,637,483, 5,904,920 and 6,350,445 describe the use of GM-CSF for treatment of tumors. Activity has been demonstrated in tumor models using a variety of immunomodulatory cytokines, including IL-4, IL-2, TNF alpha, G-CSF, IL-7, IL-6 and GM-CSF, as described in Golumbeck P T et al., Science 254:13-716, 1991; Gansbacher B et al., J. Exp. Med. 172:1217-1224, 1990; Fearon E R et al., Cell 60:397-403, 1990; Gansbacher B et al., Cancer Res. 50:7820-25, 1990; Teng M et al., PNAS 88:3535-3539, 1991; Columbo M P et al., J. Exp. Med. 174:1291-1298, 1991; Aoki et al., Proc Natl Acad Sci USA. 89(9):3850-4, 1992; Porgador A, et al., Nat Immun. 13(2-3):113-30, 1994; Dranoff G et al., PNAS 90:3539-3543, 1993; Lee C T et al., Human Gene Therapy 8:187-193, 1997; Nagai E et al., Cancer Immunol. Immonther. 47:2-80, 1998 and Chang A et al., Human Gene Therapy 11:839-850, 2000, respectively. Clinical trials employing GM-CSF-expressing autologous or allogeneic cellular vaccines (GVAX®) have commenced for treatment of prostate cancer, melanoma, lung cancer, pancreatic cancer, renal cancer, and multiple myeloma (Dummer R., Curr Opin Investig Drugs 2(6):844-8, 2001; Simons J et al., Cancer Res. 15; 59(20):5160-8, 1999; Soiffer R et al., PNAS 95:13141-13146, 1998; Simons J et al., Cancer Res. 15; 57:1537-1546, 1997; Jaffee E et al., J. Clin Oncol. 19:145-156, 2001; and Salgia R et al., J. Clin Oncol. 21:624-630, 2003; Soiffer et al. J Clin Oncol 2003 21:3343B50; Nemunaitis et al. J Natl Cancer Inst. Feb. 18, 2004 96(4):326-31).
GM-CSF-expressing autologous or allogeneic cellular cancer immunotherapies have been described previously (e.g. see U.S. Pat. Nos. 6,464,973, 6,350,445, 6,187,306, 6,033,674, 5,985,290 and 5,637,483). However, there remains a need for improved GVAX®-based immunotherapy strategies for treatment of cancer.
Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4; CD152) is an immunosuppressive molecule expressed on activated T cells and a subset of CD4+CD25+ T cells. CTLA-4 is a well-known regulator of T cell activation (Chambers, C. A. et al., Annu. Rev. Immunol. 19:565, 2001). CTLA-4 signaling has been shown to inhibit events early in T cell activation both at the level of IL-2 transcription and at the level of IL-2-independent events of the cell cycle (Brunner et al., J. Immunol., 1999, 162: 5813-5820).
CTLA-4, which binds B7-1/2 is essential for down-regulation of T-cell responses. ctla-4−/− mice have been observed to suffer from a lethal lymphoproliferative response that is initiated by uncontrolled T-cell expansion. Thus, CD28 and CTLA-4 play critical roles in regulating early stages of the T-cell response. CTLA-4 has also been shown to regulate both the occurrence and severity of experimental autoimmune disease in mice (Allison, J. P., Cancer Immunity, Vol. 5 Suppl. 1, p. 9; 6 Apr. 2005).
A fully human monoclonal antibody to human CTLA-4 has shown anti-tumor activity in Phase I/II and II trials (Medarex). In a phase I study that involved administration of a fully human CTLA-4-blocking monoclonal antibody (MDX-010) combined with melanoma peptide vaccines, eight out of nineteen patients with resected stage III or IV metastatic melanoma who received repeat doses of MDX-010 developed significant autoimmune toxicities. The symptoms included uveitis, rashes, and gastrointestinal reactions (diarrhea and abdominal pain). See, e.g., Sanderson K. et al., J Clin Oncol 23:741-750, 2005.
In another study, fourteen patients with metastatic melanoma received intravenous administration of a fully human anti-CTLA-4 antibody (MDX-010) at 3 mg/kg every 3 weeks as tolerated in conjunction with subcutaneous vaccination with two modified HLA-A 0201-restricted gp100 peptides. The results indicated that while three patients had objective cancer regression, six patients (43%) developed autoimmune events including three patients with dermatitis, two with colitis/enterocolitis and one with hepatitis, all of which were self-limited or responsive to systemic steroids. (G. Q. Phan et al., Proc Am Soc Clin Oncol 22: page 852, 2003, Abstr 3424). These data suggest that CTLA-4 may have a therapeutic benefit, however, systemic administration of anti-CTLA4 antibody sufficient to achieve to efficacy in a clinical setting may have related toxicity. Therefore, there is a need to develop compositions that overcome the potential toxicity by allowing for a lower systemic level of anti-CTLA4 antibody which is also efficacious.